Animal models of human diseases have been of tremendous value in understanding mechanisms of disease and in design of effective treatment protocols. In spite of the success of this approach in certain areas, there has been limited success in development of animal models of diminished mental capacity, especially diminished mental capacity with age. One such model, Ts65Dn, which was developed by Davisson at The Jackson Laboratory, is considered to be the best animal model of human Down syndrome. Although aspects of this model have been studied and parallels to the human condition have been drawn, potential age-related cognitive losses have not been explored. For instance, there are reports of decreased cognitive function in Ts65Dn mice, but most report on a single time period during the first half of the expected life span and most losses are neither robust nor consistently found in all studies. To more fully explore the diminished mental capacity of this model, a longitudinal study over the entire life span of the animal, as we propose here, is needed to determine the extent of additional cognitive loss as this animal model ages. Operant conditioning procedures are uniquely suited for this type of longitudinal study since behavior can be maintained and repeatedly tested in individual subjects for months to years. Recently our group, in collaboration with Dr. Davisson's group, showed a clear deficit in learning in Ts65Dn mice responding under a repeated acquisition of behavioral chains schedule of reinforcement. Specific aims 1-3 will examine the repeated learning, working memory, sustained attention, and the effect of putative cognitive enhancers on the performance of Ts65Dn and littermate controls from 3 to 24 months of age. In specific aim 4, Dr. Griffin's group will analyze the brains of Ts65Dn and littermate control animals to determine the expression of specific proteins that have been implicated in neuropathological changes and in the pathogenesis of age-related decline in cognition in humans and in experimental animals. To our knowledge, the current proposal represents the first attempt to study the behavioral phenotype of the Ts65Dn mouse using operant conditioning procedures, especially over the life span and in conjunction with neuropathological and age-related changes.